Abstract CN05-01: DNA damage signatures and practical use

Abstract

Abstract A cancer genome is a historical account of the mutagenic activity that has occurred throughout the development of the tumor. Indeed, every mutation matters. While driver mutations were the main focus of cancer research for a long time, passenger mutational signatures, the imprints of DNA damage and DNA repair processes that have been operative during tumorigenesis, are also biologically informative (1-5). We previously outlined the methods for identifying and quantifying base substitution mutational signatures present in primary human cancers (1-5). Recently, the intellectual framework of mutational signatures was extended to include six novel rearrangement signatures (6). Exploring this in >2,500 whole genome-sequenced tumors of multiple tumor types reveals how our early (and rather simplistic) thinking of mutational signatures requires critical reevaluation. There are more nuances than previously appreciated. Diving into the detail of individual mutational signatures (7), we reveal intriguing mechanistic insights into the DNA damage and repair processes that mark the landscape of cancer genomes. In some instances, our findings invite more thoughtful consideration of that relatively binary distinction between drivers and passengers. Furthermore, we demonstrate why our whole-genome profiling methods could assist in taking things to a clinical level (6-8), with mutational signatures forming an additional weapon in the arsenal of cancer diagnostics and therapeutic stratification, in the modern war against cancer.